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Marc E Buyse

IDDI 
30 avenue provinciale
1340 Louvain-la-Neuve
Belgium
marc.buyse@iddi.com
Marc Buyse is Chairman of IDDI Consultants at the International Drug Development Institute (IDDI) in Houston, TX and Associate Professor of Biostatistics at the Universiteit Hasselt, Belgium. He holds degrees in engineering and statistics from Brussels University (ULB), management from the Cranfield School of Management (Cranfield, UK) and a doctorate in biostatistics from Harvard University (Boston, MA). He was President of the International Society for Clinical Biostatistics, President of the Quetelet Society, and Fellow of the Society for Clinical Trials. He worked at the EORTC (European Organization for Research and Treatment of Cancer) in Brussels and at the Dana Farber Cancer Institute in Boston prior to founding IDDI in 1991. He currently serves on the editorial board of the journals Cancer Investigation, Clinical Trials, Biometrical Journal, Journal of Clinical Oncology, Statistical Methods in Medical Research, and Statistics in Biopharmaceutical Research.

Journal articles

2013
Marc Buyse, Stefan Michiels (2013)  Omics-based clinical trial designs.   Curr Opin Oncol Mar  
Abstract: PURPOSE OF REVIEW: The derivation of signatures using -omics technologies is increasingly integrated in the design of clinical trials in oncology. In this review, we investigate the clinical trial designs for the validation of prognostic and predictive signatures. RECENT FINDINGS: Using real-life breast cancer trial examples, we highlight the pros and cons of clinical utility designs for prognostic signatures. For predictive signatures, we first review alternative procedures to test the effect of treatment in the overall population as well as in the signature-positive or signature-negative subgroup. We proceed to show why the recent literature on signature-based strategy designs discourages the use of this design. We conclude by discussing adaptive signature designs to identify and validate a signature in a single trial using cross-validation techniques. SUMMARY: Use of -omics technologies should not be an add-on to clinical trials, it must become an integral part of their design.
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Oriana Ciani, Marc Buyse, Ruth Garside, Toby Pavey, Ken Stein, Jonathan A C Sterne, Rod S Taylor (2013)  Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study.   BMJ 346: 01  
Abstract: To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes.
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C Oakman, P A Francis, J Crown, E Quinaux, M Buyse, E De Azambuja, M Margeli Vila, M Andersson, B Nordenskjöld, R Jakesz, B Thürlimann, J Gutiérrez, V Harvey, L Punzalan, P Dell'orto, D Larsimont, I Steinberg, R D Gelber, M Piccart-Gebhart, G Viale, A Di Leo (2013)  Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.   Ann Oncol Jan  
Abstract: BackgroundIn women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes.MethodsPatients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) Ã 4 âclassical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) Ã 4 âCMF; (iii) sequential docetaxel: A (75 mg/m(2)) Ã 3 â docetaxel (T) (100 mg/m(2)) Ã 3 â CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) Ã 4 âCMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes.ResultsTwo thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers.ConclusionWith further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
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Silvy Laporte, Pierre Squifflet, Noémie Baroux, Frank Fossella, Vassilis Georgoulias, Jean-Louis Pujol, Jean-Yves Douillard, Shinzohy Kudoh, Jean-Pierre Pignon, Emmanuel Quinaux, Marc Buyse (2013)  Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials.   BMJ Open 3: 3. 03  
Abstract: To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC).
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Edith A Perez, Michael F Press, Amylou C Dueck, Robert B Jenkins, Chungyeul Kim, Beiyun Chen, Ivonne Villalobos, Soonmyung Paik, Marc Buyse, Anne E Wiktor, Reid Meyer, Melanie Finnigan, Joanne Zujewski, Mona Shing, Howard M Stern, Wilma L Lingle, Monica M Reinholz, Dennis J Slamon (2013)  Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005).   Breast Cancer Res Treat 138: 1. 99-108 Feb  
Abstract: A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC-/FISH- was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.
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J A Ajani, M Buyse, M Lichinitser, V Gorbunova, G Bodoky, J Y Douillard, S Cascinu, V Heinemann, R Zaucha, A Carrato, D Ferry, V Moiseyenko (2013)  Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study.   European journal of cancer (Oxford, England : 1990) Jul  
Abstract: The aim of developing oral fluorouracil (5-FU) is to provide a more convenient administration route with similar efficacy and the best achievable tolerance. S-1, a novel oral fluoropyrimidine, was specifically designed to overcome the limitations of intravenous fluoropyrimidine therapies.
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2012
Everardo D Saad, Marc Buyse (2012)  Non-inferiority trials in breast and non-small cell lung cancer: choice of non-inferiority margins and other statistical aspects.   Acta Oncol 51: 7. 890-896 Sep  
Abstract: Determining the non-inferiority margin is an essential step in the design and interpretation of non-inferiority trials, and this margin should be preferably justified on clinical and statistical grounds.
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Renata Duchnowska, Wojciech Biernat, Barbara Szostakiewicz, Jeff Sperinde, Fanny Piette, Mojgan Haddad, Agnes Paquet, Yolanda Lie, Bogumiła Czartoryska-Arłukowicz, Piotr Wysocki, Tomasz Jankowski, Barbara Radecka, Małgorzata Foszczynska-Kłoda, Maria Litwiniuk, Sylwia Debska, Jodi Weidler, Weidong Huang, Marc Buyse, Michael Bates, Jacek Jassem (2012)  Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.   Oncologist 17: 1. 26-35 01  
Abstract: Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab.
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David Venet, Erik Doffagne, Tomasz Burzykowski, François Beckers, Yves Tellier, Eric Genevois-Marlin, Ursula Becker, Valerie Bee, Veronique Wilson, Catherine Legrand, Marc Buyse (2012)  A statistical approach to central monitoring of data quality in clinical trials.   Clin Trials Jun  
Abstract: BACKGROUND: Classical monitoring approaches rely on extensive on-site visits and source data verification. These activities are associated with high cost and a limited contribution to data quality. Central statistical monitoring is of particular interest to address these shortcomings. PURPOSE: This article outlines the principles of central statistical monitoring and the challenges of implementing it in actual trials. METHODS: A statistical approach to central monitoring is based on a large number of statistical tests performed on all variables collected in the database, in order to identify centers that differ from the others. The tests generate a high-dimensional matrix of p-values, which can be analyzed by statistical methods and bioinformatic tools to identify extreme centers. RESULTS: Results from actual trials are provided to illustrate typical findings that can be expected from a central statistical monitoring approach, which detects abnormal patterns that were not (or could not have been) detected by on-site monitoring. LIMITATIONS: Central statistical monitoring can only address problems present in the data. Important aspects of trial conduct such as a lack of informed consent documentation, for instance, require other approaches. The results provided here are empirical examples from a limited number of studies. CONCLUSION: Central statistical monitoring can both optimize on-site monitoring and improve data quality and as such provides a cost-effective way of meeting regulatory requirements for clinical trials. Clinical Trials 2012; XX: 1 -9. http://ctj.sagepub.com.
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Pascal Piedbois, Marc Buyse (2012)  Criteria and endpoints in advanced prostate cancer.   Bull Cancer Apr  
Abstract: In castrate-refractory prostate cancers, main efficacy endpoints are progression free survival for phase-II trials and overall survival for phase-III trials. However, various progression criteria have been used, and overall survival may become more difficult to impact due to the recent approval of more effective drugs. PSA is useful in clinical practice, provided it is interpreted with caution, but cannot be used as a surrogate endpoint in clinical trials. Finally, circulating tumor cells represent a promising area of development.
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Lynnette Fernández-Cuesta, Catherine Oakman, Priscila Falagan-Lotsch, Ke-Seay Smoth, Emmanuel Quinaux, Marc Buyse, M Stella Dolci, Evandro De Azambuja, Pierre Hainaut, Patrizia Dell'orto, Denis Larsimont, Prudence A Francis, John Crown, Martine Piccart-Gebhart, Giuseppe Viale, Angelo Di Leo, Magali Olivier (2012)  Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.   Breast Cancer Res 14: 3. 05  
Abstract: Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel.
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Stuart G Baker, Daniel J Sargent, Marc Buyse, Tomasz Burzykowski (2012)  Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time.   Biometrics 68: 1. 248-257 Mar  
Abstract: Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download.
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Sara A Hurvitz, David J Betting, Howard M Stern, Emmanuel Quinaux, Jeremy Stinson, Somasekar Seshagiri, Ying Zhao, Marc Buyse, John Mackey, Adrian Driga, Sambasivarao Damaraju, Mark X Sliwkowski, Nicholas J Robert, Vicente Valero, John Crown, Carla Falkson, Adam Brufsky, Tadeusz Pienkowski, Wolfgang Eiermann, Miguel Martin, Valerie Bee, Omkar Marathe, Dennis J Slamon, John M Timmerman (2012)  Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients.   Clin Cancer Res 18: 12. 3478-3486 Jun  
Abstract: The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer.
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Marta Pestrin, Silvia Bessi, Fabio Puglisi, Alessandro M Minisini, Giovanna Masci, Nicola Battelli, Alberto Ravaioli, Lorenzo Gianni, Roberta Di Marsico, Carlo Tondini, Stefania Gori, Charles R Coombes, Justin Stebbing, Laura Biganzoli, Marc Buyse, Angelo Di Leo (2012)  Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study.   Breast Cancer Res Treat 134: 1. 283-289 Jul  
Abstract: This multicenter phase II trial was designed to evaluate the activity of lapatinib in metastatic breast cancer patients with HER2-negative primary tumors and HER2-positive circulating tumor cells (CTCs). In this study MBC patients with HER2-negative primary tumors and HER2-positive CTCs previously treated with at least a first-line therapy for metastatic disease received lapatinib 1500 mg/day. The CellSearch System® was used for CTCs isolation and bio-characterization. HER2 status was assessed on CTCs by immunofluorescence. A case was defined as CTCs positive if â¥2 CTC/7.5 ml of blood were isolated and HER2-positive if â¥50% of CTCs were HER2-positive. 139 HER2-negative patients were screened, 96 patients were positive for CTCs (mean number of CTCs: 85; median number of CTCs: 19; range 2-1637). Seven of the 96 patients (7%) had â¥50% HER2-positive CTCs and were eligible for treatment with lapatinib. No objective tumor responses occurred in this population. In one patient, disease stabilization lasting 254 days (8.5 months) was observed. From the findings of this study, we concluded that a subset of patients with a HER2-negative primary tumor presents HER2-positive CTCs during disease progression, although the HER2 shift rate seems to be lower than previously reported. Despite the lack of objective response, the durable disease stabilization observed in one patient cannot rule out the hypothesis that lapatinib may have some activity in this patient population. However, considering that only 1/139 screened patients may potentially have derived benefit from this approach, future trials designed according to the presented strategy cannot be recommended.
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2011
Michael F Press, Guido Sauter, Marc Buyse, Leslie Bernstein, Roberta Guzman, Angela Santiago, Ivonne E Villalobos, Wolfgang Eiermann, Tadeusz Pienkowski, Miguel Martin, Nicholas Robert, John Crown, Valerie Bee, Henry Taupin, Kerry J Flom, Isabelle Tabah-Fisch, Giovanni Pauletti, Mary-Ann Lindsay, Alessandro Riva, Dennis J Slamon (2011)  Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.   J Clin Oncol 29: 7. 859-867 Mar  
Abstract: Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers.
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Marc Buyse, Stefan Michiels, Daniel J Sargent, Axel Grothey, Alastair Matheson, Aimery de Gramont (2011)  Integrating biomarkers in clinical trials.   Expert Rev Mol Diagn 11: 2. 171-182 Mar  
Abstract: Biomarkers have a growing role in clinical trials. With the advent of the targeted therapy era, molecular biomarkers in particular are becoming increasingly important within both clinical research and clinical practice. This article focuses on biomarkers that anticipate the prognosis of individual patients ('prognostic' biomarkers) and on biomarkers that predict how individual patients will respond to specific treatments ('predictive' biomarkers, also called 'effect modifiers'). Specific Phase II and III clinical trial designs are discussed in detail for their ability to validate the biomarker and/or to establish the effect of an experimental therapy in patient populations defined by the presence or absence of the biomarker. Contemporary biomarker-based clinical trials in oncology are used as examples.
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S Gill, S Berry, J Biagi, C Butts, M Buyse, E Chen, D Jonker, C Mărginean, B Samson, J Stewart, M Thirlwell, R Wong, J A Maroun (2011)  Progression-free survival as a primary endpoint in clinical trials of metastatic colorectal cancer.   Curr Oncol 18 Suppl 2: S5-S10 Oct  
Abstract: In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the "gold standard"-the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer.
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Marc Buyse, Pierre Squifflet, Beverly J Lange, Todd A Alonzo, Richard A Larson, Jonathan E Kolitz, Stephen L George, Clara D Bloomfield, Sylvie Castaigne, Sylvie Chevret, Didier Blaise, Dominique Maraninchi, Kathryn J Lucchesi, Tomasz Burzykowski (2011)  Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.   Blood 117: 26. 7007-7013 Jun  
Abstract: IL-2 is a natural, T cell-derived cytokine that stimulates the cytotoxic functions of T and natural killer cells. IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (N = 905) and summary data from a sixth RCT (N = 550). Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR < 1 indicating treatment benefit. Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; P = .74) or overall survival (HR = 1.08; P = .39). Analyses including the sixth RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, P = .52; overall survival HR = 1.06; P = .46). No significant heterogeneity was found between the trials. Prespecified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy. We conclude that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.
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Benoist Chibaudel, Franck Bonnetain, Qian Shi, Marc Buyse, Christophe Tournigand, Daniel J Sargent, Carmen J Allegra, Richard M Goldberg, Aimery de Gramont (2011)  Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy--an Aide et Recherche en Cancerologie Digestive Group Study.   J Clin Oncol 29: 31. 4199-4204 Nov  
Abstract: Progression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS).
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Tomasz Burzykowski, M Buyse (2011)  The correlation structure of longitudinal measurements of vision in patients with macular degeneration.   Pharm Stat 10: 2. 115-121 Mar/Apr  
Abstract: In age-related macular degeneration (ARMD) trials, the FDA-approved endpoint is the loss (or gain) of at least three lines of vision as compared to baseline. The use of such a response endpoint entails a potentially severe loss of information. A more efficient strategy could be obtained by using longitudinal measures of the change in visual acuity. In this paper we investigate, by using data from two randomized clinical trials, the mean and variance-covariance structures of the longitudinal measurements of the change in visual acuity.
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Angelo Di Leo, Christine Desmedt, John M S Bartlett, Fanny Piette, Bent Ejlertsen, Kathleen I Pritchard, Denis Larsimont, Christopher Poole, Jorma Isola, Helena Earl, Henning Mouridsen, Frances P O'Malley, Fatima Cardoso, Minna Tanner, Alison Munro, Chris J Twelves, Christos Sotiriou, Lois Shepherd, David Cameron, Martine J Piccart, Marc Buyse (2011)  HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data.   Lancet Oncol 12: 12. 1134-1142 Nov  
Abstract: Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.
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Wolfgang Eiermann, Tadeusz Pienkowski, John Crown, Saeed Sadeghi, Miguel Martin, Arlene Chan, Mansoor Saleh, Sandeep Sehdev, Louise Provencher, Vladimir Semiglazov, Michael Press, Guido Sauter, Mary-Ann Lindsay, Alessandro Riva, Marc Buyse, Philippe Drevot, Henry Taupin, John R Mackey (2011)  Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.   J Clin Oncol 29: 29. 3877-3884 Oct  
Abstract: Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC.
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S R Brown, W M Gregory, C J Twelves, M Buyse, F Collinson, M Parmar, M T Seymour, J M Brown (2011)  Designing phase II trials in cancer: a systematic review and guidance.   Br J Cancer 105: 2. 194-199 Jul  
Abstract: Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design.
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A M Oza, V Castonguay, D Tsoref, I Diaz-Padilla, K Karakasis, H Mackay, S Welch, J Weberpals, P Hoskins, M Plante, D Provencher, K Tonkin, A Covens, P Ghatage, J Gregoire, H Hirte, D Miller, B Rosen, J Maroun, M Buyse, C Coens, M F Brady, G C E Stuart (2011)  Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.   Curr Oncol 18 Suppl 2: S20-S27 Oct  
Abstract: Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.
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Priya Rastogi, Marc E Buyse, Sandra M Swain, Samuel A Jacobs, André Robidoux, Marcia K Liepman, Eduardo R Pajon, Philip A Dy, Juan G Posada, Marianne K Melnik, Fanny Piette, Charles E Geyer, Elfetherios P Mamounas, Norman Wolmark (2011)  Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group.   Clin Breast Cancer 11: 4. 228-234 Aug  
Abstract: Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer (MBC). The purpose of this trial was to determine the activity and safety profile of neoadjuvant bevacizumab with chemotherapy in women with locally advanced breast cancer (LABC).
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Elisabeth Quoix, Rodryg Ramlau, Virginie Westeel, Zsolt Papai, Anne Madroszyk, Alain Riviere, Piotr Koralewski, Jean-Luc Breton, Erich Stoelben, Denis Braun, Didier Debieuvre, Hervé Lena, Marc Buyse, Marie-Pierre Chenard, Bruce Acres, Gisèle Lacoste, Bérangère Bastien, Annette Tavernaro, Nadine Bizouarne, Jean-Yves Bonnefoy, Jean-Marc Limacher (2011)  Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.   Lancet Oncol 12: 12. 1125-1133 Nov  
Abstract: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC.
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Marc Buyse, Pierre Squifflet, Kathryn J Lucchesi, Mats L Brune, Sylvie Castaigne, Jacob M Rowe (2011)  Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia.   Trials 12: 03  
Abstract: Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.
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Christine Desmedt, Angelo Di Leo, Evandro de Azambuja, Denis Larsimont, Benjamin Haibe-Kains, Jean Selleslags, Suzette Delaloge, Caroline Duhem, Jean-Pierre Kains, Birgit Carly, Marie Maerevoet, Anita Vindevoghel, Ghislane Rouas, Françoise Lallemand, Virginie Durbecq, Fatima Cardoso, Roberto Salgado, Rodrigo Rovere, Gianluca Bontempi, Stefan Michiels, Marc Buyse, Jean-Marie Nogaret, Yuan Qi, Fraser Symmans, Lajos Pusztai, Véronique D'Hondt, Martine Piccart-Gebhart, Christos Sotiriou (2011)  Multifactorial approach to predicting resistance to anthracyclines.   J Clin Oncol 29: 12. 1578-1586 Apr  
Abstract: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.
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Dennis Slamon, Wolfgang Eiermann, Nicholas Robert, Tadeusz Pienkowski, Miguel Martin, Michael Press, John Mackey, John Glaspy, Arlene Chan, Marek Pawlicki, Tamas Pinter, Vicente Valero, Mei-Ching Liu, Guido Sauter, Gunter von Minckwitz, Frances Visco, Valerie Bee, Marc Buyse, Belguendouz Bendahmane, Isabelle Tabah-Fisch, Mary-Ann Lindsay, Alessandro Riva, John Crown (2011)  Adjuvant trastuzumab in HER2-positive breast cancer.   N Engl J Med 365: 14. 1273-1283 Oct  
Abstract: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.
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Marc Buyse, Stefan Michiels, Pierre Squifflet, Kathryn J Lucchesi, Kristoffer Hellstrand, Mats L Brune, Sylvie Castaigne, Jacob M Rowe (2011)  Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission.   Haematologica 96: 8. 1106-1112 Aug  
Abstract: In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia.
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D Sargent, Q Shi, G Yothers, E Van Cutsem, J Cassidy, L Saltz, N Wolmark, B Bot, A Grothey, M Buyse, A de Gramont (2011)  Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: Data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803.   Eur J Cancer 47: 7. 990-996 May  
Abstract: BACKGROUND: The ACCENT group previously established disease-free survival (DFS) with 2 or 3years median follow-up to predict 5year overall survival (5year OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between end-points in trials with oral fluoropyrimidines, oxaliplatin and irinotecan is unknown. METHODS: Associations between the treatment effect hazard ratios (HRs) on 2 and 3years DFS, and 5 and 6years OS were examined in 6 phase III trials not included in prior analyses from 1997 to 2002. Individual data for 12,676 patients were analysed; two trials each tested oxaliplatin, irinotecan and oral treatment versus 5-FU/LV. FINDINGS: Overall association between 2/3year DFS and 5/6year OS HRs was modest to poor (simple R(2) measures: 0.58-0.76, model-based R(2): 0.17-0.49). In stage III patients, the association increased (model-based R(2)⩾0.79). Observed treatment effects on 2year DFS accurately 5/6year OS effects overall and in stage III patients. INTERPRETATION: In recent trials of cytotoxic chemotherapy, 2 or 3years DFS HRs are highly predictive of 5 and 6years OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6year OS, thus at least 6year follow-up is recommended to assess OS benefit. These data support DFS as the primary end-point for stage III colon cancer trials testing cytotoxic agents.
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2010
Aimery de Gramont, Joleen Hubbard, Qian Shi, Michael J O'Connell, Marc Buyse, Jacqueline Benedetti, Brian Bot, Chris O'Callaghan, Greg Yothers, Richard M Goldberg, Charles D Blanke, Al Benson, Qiqi Deng, Steven R Alberts, Thierry Andre, Norman Wolmark, Axel Grothey, Daniel Sargent (2010)  Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the 20,800 patient ACCENT data set.   J Clin Oncol 28: 3. 460-465 Jan  
Abstract: PURPOSE: We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. METHODS: The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. RESULTS: Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R(2) = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R(2) = 0.67 for both 2- and 3-year DFS) and 7-year OS (R(2) = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. CONCLUSION: Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.
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Mitch Dowsett, Jack Cuzick, Jim Ingle, Alan Coates, John Forbes, Judith Bliss, Marc Buyse, Michael Baum, Aman Buzdar, Marco Colleoni, Charles Coombes, Claire Snowdon, Michael Gnant, Raimund Jakesz, Manfred Kaufmann, Francesco Boccardo, Jon Godwin, Christina Davies, Richard Peto (2010)  Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen.   J Clin Oncol 28: 3. 509-518 Jan  
Abstract: PURPOSE: To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2). MATERIALS AND METHODS: Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive. Log-rank P values are two-sided. RESULTS: Cohort 1 comprised 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute 2.9% (SE = 0.7%) decrease in recurrence (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a nonsignificant absolute 1.1% (SE = 0.5%) decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1). Cohort 2 comprised 9,015 patients with a mean of 3.9 years of follow-up. At 3 years from treatment divergence (ie, approximately 5 years after starting hormonal treatment), AI therapy was associated with an absolute 3.1% (SE = 0.6%) decrease in recurrence (5.0% for AI v 8.1% for tamoxifen since divergence; 2P < .00001) and an absolute 0.7% (SE = 0.3%) decrease in breast cancer mortality (1.7% for AI v 2.4% for tamoxifen since divergence; 2P = .02). There was no convincing heterogeneity in the proportional recurrence reduction with respect to age, nodal status, tumor grade, or progesterone receptor status and no indication of an increase in nonbreast deaths with AIs in either cohort. CONCLUSION AIs produce significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after 2 to 3 years of tamoxifen. Additional follow-up will provide clearer information on long-term survival.
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E D Saad, A Katz, P M Hoff, M Buyse (2010)  Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.   Ann Oncol 21: 1. 7-12 Jan  
Abstract: Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.
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Marc Buyse, Daniel J Sargent, Axel Grothey, Alastair Matheson, Aimery de Gramont (2010)  Biomarkers and surrogate end points--the challenge of statistical validation.   Nat Rev Clin Oncol 7: 6. 309-317 Jun  
Abstract: Biomarkers and surrogate end points have great potential for use in clinical oncology, but their statistical validation presents major challenges, and few biomarkers have been robustly confirmed. Provisional supportive data for prognostic biomarkers, which predict the likely outcome independently of treatment, is possible through small retrospective studies, but it has proved more difficult to achieve robust multi-site validation. Predictive biomarkers, which predict the likely response of patients to specific treatments, require more extensive data for validation, specifically large randomized clinical trials and meta-analysis. Surrogate end points are even more challenging to validate, and require data demonstrating both that the surrogate is prognostic for the true end point independently of treatment, and that the effect of treatment on the surrogate reliably predicts its effect on the true end point. In this Review, we discuss the nature of prognostic and predictive biomarkers and surrogate end points, and examine the statistical techniques and designs required for their validation. In cases where the statistical requirements for validation cannot be rigorously achieved, the biological plausibility of an end point or surrogate might support its adoption. No consensus yet exists on processes or standards for pragmatic evaluation and adoption of biomarkers and surrogate end points in the absence of robust statistical validation.
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Geert Molenberghs, Tomasz Burzykowski, Ariel Alonso, Pryseley Assam, Abel Tilahun, Marc Buyse (2010)  A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.   Stat Methods Med Res 19: 3. 205-236 Jun  
Abstract: For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.
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Marc Buyse (2010)  Generalized pairwise comparisons of prioritized outcomes in the two-sample problem.   Stat Med 29: 30. 3245-3257 Dec  
Abstract: This paper extends the idea behind the U-statistic of the Wilcoxon-Mann-Whitney test to perform generalized pairwise comparisons between two groups of observations. The observations are outcomes captured by a single variable, possibly repeatedly measured, or by several variables of any type (e.g. discrete, continuous, time to event). When several outcomes are considered, they must be prioritized. We show that generalized pairwise comparisons extend well-known non-parametric tests, and illustrate their interest using data from two randomized clinical trials. We also show that they lead to a general measure of the difference between the groups called the 'proportion in favor of treatment', denoted Î, which is related to traditional measures of treatment effect for a single variable.
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Everardo D Saad, Artur Katz, Marc Buyse (2010)  Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials.   J Clin Oncol 28: 11. 1958-1962 Apr  
Abstract: With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression.
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Isabelle Baumgaertner, Emmanuel Quinaux, Ahmed Khalil, Christophe Louvet, Marc Buyse, Aimery de Gramont, Thierry André (2010)  Comparison of the levogyre and dextro-levogyre forms of leucovorin in a phase III trial of bimonthly LV5FU2 versus monthly 5-fluorouracil and high-dose leucovorin for patients with stage II and III colon cancer (GERCOR C96.1).   Clin Colorectal Cancer 9: 2. E5-10 Apr  
Abstract: BACKGROUND: These analyses compare the safety and efficacy of 2 forms (levogyre [L] and dextro-levogyre [DL]) of leucovorin (LV) when used with 5-fluorouracil (5-FU) for the adjuvant treatment of patients with stage II and III colon cancer. MATERIALS AND METHODS: The analysis used primary efficacy and safety data of a phase III trial comparing monthly 5-FU/LV or bimonthly LV5FU2 (LV 200 mg/m2 intravenously over 2 hours followed by 5-FU 400 mg/m2 bolus and then 600 mg/m2 continuous intravenous infusion over 22 hours, days 1 and 2, every 2 weeks). In both regimens, depending on the choice made by each center, patients received either DL-LV (200 mg/m2) or L-LV (100 mg/m2). RESULTS: L-LV and DL-LV were administered respectively to 60% (n = 519) and 40% (n = 357) of the patients. Important prognostic characteristics were well balanced between the 2 groups. The proportion of any grade 3/4 toxicity was 20% in the L-LV group and 17% in the DL-LV group. There was no statistical difference in terms of toxicity between the 2 groups. The median follow-up time was 6.1 years. There were no statistically significant differences between L-LV and DL-LV in terms of either disease-free survival (66.7% vs. 67.2%; hazard ratio [HR], 1.03; 95% CI, 0.82-1.31; P = .78) or overall survival (78.2% vs. 74.5%; HR, 1.28; 95% CI, 0.97-1.69; P = .078). CONCLUSION: This study supports the use of either DL (200 mg/m2) or L (100 mg/m2) LV in association with 5-FU as adjuvant treatment of patients with colon cancer.
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Xavier Paoletti, Koji Oba, Tomasz Burzykowski, Stefan Michiels, Yasuo Ohashi, Jean-Pierre Pignon, Philippe Rougier, Junichi Sakamoto, Daniel Sargent, Mitsuru Sasako, Eric Van Cutsem, Marc Buyse (2010)  Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis.   JAMA 303: 17. 1729-1737 May  
Abstract: CONTEXT: Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking. OBJECTIVES: To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments. DATA SOURCES: Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings. STUDY SELECTION: All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified. DATA EXTRACTION: As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years. RESULTS: There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy. CONCLUSION: Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.
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Pascal Piedbois, Marc Buyse (2010)  Meta-analysis based on individual patient data: example of advanced colorectal cancer   Rech Soins Infirm 101. 25-28 Jun  
Abstract: The authors mention the existing methods to perform meta-analysis, and show that meta-analysis based on individual patient data (IPD meta-analyses) are the most reliable. Taking the example of 4 successive meta-analysis of clinical trials in advanced colorectal cancer, they illustrate the possibilities of IPD meta-analysis. They conclude that meta-analysis are a powerful tool not only to confirm small differences between treatment modalities, but also to generate hypothesis, to perform exploratory subgroup analysis, and to study potential surrogate endpoints.
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2009
B Chibaudel, C Tournigand, P Artru, T André, A Cervantes, A Figer, G Lledo, M Flesch, M Buyse, L Mineur, E Carola, F Rivera, N Perez-Staub, C Louvet, A de Gramont (2009)  FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study.   Ann Oncol 20: 8. 1383-1386 Aug  
Abstract: BACKGROUND: Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. PATIENTS AND METHODS: Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level <or=3 ULN versus 3-5 ULN. RESULTS: Among the 620 patients in OPTIMOX1 study, 63 had ALP 3-5 ULN; 33 in arm A and 30 in arm B. The response rate in these patients was 56% versus 59% in patients with ALP <or=3 ULN. Median progression-free survival and overall survival were, respectively, 6.4 and 11.5 months in patients with ALP 3-5 ULN and 9.0 and 21.1 months in patients with ALP <or=3 ULN. Thirty-three percent of the patients in the cohort experienced grade 3/4 toxicity. CONCLUSION: Both FOLFOX regimens achieved high tumor response rates and offer good palliation in MCRC patients with a poor prognosis.
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Marc Buyse (2009)  Contributions of meta-analyses based on individual patient data to therapeutic progress in colorectal cancer.   Int J Clin Oncol 14: 2. 95-101 Apr  
Abstract: Meta-analysis is the statistical process of combining information from several studies addressing the same question. Meta-analyses based on individual patient data are far more reliable and informative than those based on summary statistics obtained from the trialists or extracted from the published literature. Meta-analysis of randomized clinical trials may contribute to therapeutic progress through (1) establishing efficacy benefits beyond a reasonable doubt, (2) identifying sources of heterogeneity between trials, (3) studying subsets reliably, (4) confirming differences in toxicity profiles, (5) evaluating the cost-effectiveness of experimental therapies, (6) assessing surrogate endpoints, and (7) addressing ancillary questions. All of these potential contributions are illustrated with examples in early and advanced colorectal cancer.
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Christine Desmedt, Jeff Sperinde, Fanny Piette, Weidong Huang, Xueguang Jin, Yuping Tan, Virginie Durbecq, Denis Larsimont, Rosa Giuliani, Colombe Chappey, Marc Buyse, John Winslow, Martine Piccart, Christos Sotiriou, Christos Petropoulos, Michael Bates (2009)  Quantitation of HER2 expression or HER2:HER2 dimers and differential survival in a cohort of metastatic breast cancer patients carefully selected for trastuzumab treatment primarily by FISH.   Diagn Mol Pathol 18: 1. 22-29 Mar  
Abstract: The selection of patients with HER2-positive breast cancer for treatment with trastuzumab is based on the measurement of HER2 protein expression by immunohistochemistry, or the presence of HER2 gene amplification by fluorescence in situ hybridization (FISH). By using multivariate analyses, we investigate the relationship between quantitative measurements of HER2 expression or HER2:HER2 dimers and objective response (Response Evaluation Criteria in Solid Tumors), time to progression, and breast cancer survival after trastuzumab treatment in a cohort of patients with metastatic breast cancer who were primarily selected for treatment by FISH. The VeraTag assay, a proximity-based assay designed to quantitate protein expression and dimerization in formalin-fixed, paraffin-embedded tissue specimens, was used to measure HER2 protein expression and HER2:HER2 dimer levels. In a Cox proportional hazards analysis, higher HER2 expression or HER2:HER2 dimer levels were both correlated with longer survival (P=0.0058 and P=0.016, respectively) after treatment with trastuzumab in a population of patients that were either FISH-positive (90%) or immunohistochemistry 3+ (10%). Patients with higher levels of HER2 expression or HER2:HER2 dimers seemed to derive little benefit from the addition of concomitant chemotherapy to trastuzumab, whereas those with lower levels benefited significantly [interaction test P=0.43 (HER2 expression), P=0.27 (HER2:HER2 dimers)]. These data suggest that more quantitative or functional measurements of HER2 status may facilitate the development of more personalized treatment strategies for patients with metastatic breast cancer.
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Daniel Sargent, Alberto Sobrero, Axel Grothey, Michael J O'Connell, Marc Buyse, Thierry Andre, Yan Zheng, Erin Green, Roberto Labianca, Chris O'Callaghan, Jean Francois Seitz, Guido Francini, Daniel Haller, Greg Yothers, Richard Goldberg, Aimery de Gramont (2009)  Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials.   J Clin Oncol 27: 6. 872-877 Feb  
Abstract: PURPOSE: Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. METHODS: The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. RESULTS: A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. CONCLUSION: Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value.
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Marc Buyse (2009)  Use of meta-analysis for the validation of surrogate endpoints and biomarkers in cancer trials.   Cancer J 15: 5. 421-425 Sep/Oct  
Abstract: This article discusses statistical approaches to the validation of surrogate biomarkers and endpoints. One approach that has been successfully used in oncology consists of estimating associations at two levels: the association between the surrogate and the clinical endpoint, called the individual-level association, and the association between the effects of treatment on the surrogate and the clinical endpoint, called the trial-level association. This approach requires data to be available from multiple randomized trials, such as in a meta-analysis of trials based on individual patient data. The approach is illustrated using randomized trials of first-line treatments for advanced tumors of the colon, breast, ovary, and prostate. Data from several meta-analyses suggest that progression-free survival is an acceptable surrogate in advanced colorectal and ovarian cancer, but not in breast and prostate cancer.
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H Piessevaux, M Buyse, W De Roock, H Prenen, M Schlichting, E Van Cutsem, S Tejpar (2009)  Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial).   Ann Oncol 20: 8. 1375-1382 Aug  
Abstract: BACKGROUND: Early radiological tumor shrinkage may be associated with better long-term outcome in chemorefractory metastatic colorectal cancer (cmCRC) treated with cetuximab. We aimed at validating this in a large and independent series. PATIENTS AND METHODS: Of the 329 patients, 289 had a measurement both at baseline and week 6. Tumor shrinkage was expressed as a relative decrease compared with baseline and categorized according to a previously reported cut-off value ( approximately 10%) or used as a continuous variable. RESULTS: Median time to progression (TTP) was 6.1 [95% confidence interval (CI) 5.1-7.2] versus 1.5 months (95% CI 1.4-1.7) in patients with [99 patients (34.3%)] or without [190 patients (65.7%)] tumor shrinkage, respectively, at week 6 [hazard ratio (HR) 0.23 (95% CI 0.17-0.32)]. The median overall survival (OS) was 13.7 (CI NA) versus 6.9 months (95% CI 6.1-7.7) [HR 0.21 (95% CI 0.14-0.32)], respectively. In a multivariate model, early tumor decrease outperformed skin toxicity as a predictor of long-term outcome. CONCLUSIONS: Tumor shrinkage at 6 weeks is a strong predictor of TTP and OS in cmCRC patients treated with cetuximab with or without irinotecan. This suggests early tumor shrinkage is the hallmark of efficacy of cetuximab and reliably identifies the subpopulation that is sensitive to the drug. Early tumor shrinkage can be used as a marker of efficacy in clinical practice, as such or in combination.
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Stefan Michiels, Aurélie Le Maître, Marc Buyse, Tomasz Burzykowski, Emilie Maillard, Jan Bogaerts, Jan B Vermorken, Wilfried Budach, Thomas F Pajak, Kian K Ang, Jean Bourhis, Jean-Pierre Pignon (2009)  Surrogate endpoints for overall survival in locally advanced head and neck cancer: meta-analyses of individual patient data.   Lancet Oncol 10: 4. 341-350 Apr  
Abstract: BACKGROUND: The gold standard endpoint in randomised trials of locally advanced head and neck squamous-cell carcinoma (HNSCC) is overall survival. Our objective was to study whether duration of locoregional control or event-free survival (EFS) could be considered as surrogate endpoints to estimate the effect of radiotherapy and chemotherapy on overall survival. This would allow a reduction in the duration and cost of the development of new treatments. METHODS: Individual patient data from 104 trials (22 744 patients), with 116 treatment-control comparisons, from four meta-analyses on hyperfractionated or accelerated radiotherapy and concomitant, induction, or adjuvant chemotherapy were analysed. Duration of locoregional control was defined as the time from randomisation to the first locoregional event and EFS as the time to any first event (ie, locoregional relapse, distant recurrence, or death). At the individual level, a rank correlation coefficient between the surrogate endpoint and overall survival was used to assess surrogacy; at the trial level, a correlation coefficient R between treatment effects was used. FINDINGS: At the individual level, overall survival was more strongly correlated with EFS (range of correlations 0.82-0.90) than with locoregional control (0.65-0.76). For radiotherapy, treatment effects on both locoregional control and EFS were strongly correlated with those on overall survival (R=0.94 and 0.98, respectively). For chemotherapy, the correlations between treatment effects on EFS and overall survival were stronger than those between locoregional control and overall survival (range of R 0.79-0.93 vs 0.53-0.84, respectively). INTERPRETATION: EFS is a better correlate with overall survival than locoregional control and could be used as a surrogate for overall survival to assess the treatment effect of radiotherapy and chemotherapy in randomised trials of locally advanced HNSCC.
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2008
Martine J Piccart-Gebhart, Tomasz Burzykowski, Marc Buyse, George Sledge, James Carmichael, Hans-Joachim Lück, John R Mackey, Jean-Marc Nabholtz, Robert Paridaens, Laura Biganzoli, Jacek Jassem, Marijke Bontenbal, Jacques Bonneterre, Stephen Chan, Gul Atalay Basaran, Patrick Therasse (2008)  Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer.   J Clin Oncol 26: 12. 1980-1986 Apr  
Abstract: PURPOSE: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. PATIENTS AND METHODS: Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. RESULTS: Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. CONCLUSION: Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.
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Marc Buyse, Tomasz Burzykowski, Stefan Michiels, Kevin Carroll (2008)  Individual- and trial-level surrogacy in colorectal cancer.   Stat Methods Med Res 17: 5. 467-475 Oct  
Abstract: Two conditions must be fulfilled for an intermediate endpoint to be an acceptable surrogate for a true clinical endpoint: (1) there must be a strong association between the surrogate and the true endpoint, and (2) there must be a strong association between the effects of treatment on the surrogate and the true endpoint. We test whether these conditions are fulfilled for disease-free survival (DFS) and progression-free survival (PFS) on data from 20 clinical trials comparing experimental treatments with standard treatments for early and advanced colorectal cancer. The effects of treatment on DFS (or PFS in advanced disease) and OS were quantified through log hazard ratios (log HR), estimated through a Weibull model stratified for trial. The rank correlation coefficients between DFS and OS, and trial-specific treatment effects, were estimated using a bivariate copula distribution for these endpoints. A linear regression model between the estimated log hazard ratios was used to compute the "surrogate threshold effect", which is the minimum treatment effect on DFS required to predict a non-zero treatment effect on OS in a future trial. In early disease, the rank correlation coefficient between DFS and OS was equal to 0.96 (CI 0.95-0.97). The correlation coefficient between the log hazard ratios was equal to 0.94 (CI 0.87-1.01). The risk reductions were approximately 3% smaller on OS than on DFS, and the surrogate threshold effect corresponded to a DFS hazard ratio of 0.93. In advanced disease, the rank correlation coefficient between PFS and OS was equal to 0.82 (CI 0.82-0.83). The correlation coefficient between the log hazard ratios was equal to 0.99 (CI 0.94-1.04). The risk reductions were approximately 19% smaller on OS than on PFS, and the surrogate threshold effect corresponded to a PFS hazard ratio of 0.86. One trial with a large treatment effect on PFS and OS had a strong influence on the results in advanced disease. DFS (and PFS in advanced disease) are acceptable surrogates for OS in colorectal cancer.
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Tomasz Burzykowski, Marc Buyse, Martine J Piccart-Gebhart, George Sledge, James Carmichael, Hans-Joachim Lück, John R Mackey, Jean-Marc Nabholtz, Robert Paridaens, Laura Biganzoli, Jacek Jassem, Marijke Bontenbal, Jacques Bonneterre, Stephen Chan, Gul Atalay Basaran, Patrick Therasse (2008)  Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.   J Clin Oncol 26: 12. 1987-1992 Apr  
Abstract: PURPOSE: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer. PATIENTS AND METHODS: Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points. RESULTS: Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative. CONCLUSION: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.
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Benjamin Haibe-Kains, Christine Desmedt, Fanny Piette, Marc Buyse, Fatima Cardoso, Laura Van't Veer, Martine Piccart, Gianluca Bontempi, Christos Sotiriou (2008)  Comparison of prognostic gene expression signatures for breast cancer.   BMC Genomics 9: 08  
Abstract: BACKGROUND: During the last years, several groups have identified prognostic gene expression signatures with apparently similar performances. However, signatures were never compared on an independent population of untreated breast cancer patients, where risk assessment was computed using the original algorithms and microarray platforms. RESULTS: We compared three gene expression signatures, the 70-gene, the 76-gene and the Gene expression Grade Index (GGI) signatures, in terms of predicting distant metastasis free survival (DMFS) for the individual patient. To this end, we used the previously published TRANSBIG independent validation series of node-negative untreated primary breast cancer patients. We observed agreement in prediction for 135 of 198 patients (68%) when considering the three signatures. When comparing the signatures two by two, the agreement in prediction was 71% for the 70- and 76-gene signatures, 76% for the 76-gene signature and the GGI, and 88% for the 70-gene signature and the GGI. The three signatures had similar capabilities of predicting DMFS and added significant prognostic information to that provided by the classical parameters. CONCLUSION: Despite the difference in development of these signatures and the limited overlap in gene identity, they showed similar prognostic performance, adding to the growing evidence that these prognostic signatures are of clinical relevance.
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Christine Desmedt, Benjamin Haibe-Kains, Pratyaksha Wirapati, Marc Buyse, Denis Larsimont, Gianluca Bontempi, Mauro Delorenzi, Martine Piccart, Christos Sotiriou (2008)  Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.   Clin Cancer Res 14: 16. 5158-5165 Aug  
Abstract: PURPOSE: Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated according to the previously described molecular subtypes based on the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes. EXPERIMENTAL DESIGN: We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with clinical variables and several prognostic signatures on publicly available microarray studies (>2,100 patients). RESULTS: Multivariate analysis showed that in the ER+/HER2- subgroup, only the proliferation module and the histologic grade were significantly associated with clinical outcome. In the ER-/HER2- subgroup, only the immune response module was associated with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance was limited to the ER+/HER2- subgroup. CONCLUSIONS: Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2- subtype and the common denominator of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated with prognosis in the ER-/HER2- and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models and to identify new therapeutic strategies in the specific molecular subgroups.
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Colin Baigent, Frank E Harrell, Marc Buyse, Jonathan R Emberson, Douglas G Altman (2008)  Ensuring trial validity by data quality assurance and diversification of monitoring methods.   Clin Trials 5: 1. 49-55  
Abstract: Errors in the design, the conduct, the data collection process, and the analysis of a randomized trial have the potential to affect not only the safety of the patients in the trial, but also, through the introduction of bias, the safety of future patients. Trial monitoring, defined broadly to include methods of oversight which begin when the study is designed and continue until it is reported in a publication, has a role to play in eliminating such errors. On-site monitoring can be extremely inefficient for the identification of errors most likely to compromise patient safety or bias study results. However, a variety of other monitoring strategies offer alternatives to on-site monitoring. Each new trial should conduct a risk assessment to identify the optimal means of monitoring, taking into account the likely sources of error, their consequences for patients, the study's validity, and the available resources. Trial management committees should consider central statistical monitoring a key aspect of such monitoring. The systematic application of this approach would be likely to lead to tangible benefits, and resources that are currently wasted on inefficient on-site monitoring could be diverted to increasing trial sample sizes or conducting more trials.
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Pascal Piedbois, Marc Buyse (2008)  Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.   Curr Opin Oncol 20: 4. 466-471 Jul  
Abstract: PURPOSE OF REVIEW: The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. RECENT FINDINGS: Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. SUMMARY: The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.
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Tomasz Burzykowski, Marc Buyse, Greg Yothers, Junichi Sakamoto, Dan Sargent (2008)  Exploring and validating surrogate endpoints in colorectal cancer.   Lifetime Data Anal 14: 1. 54-64 Mar  
Abstract: Sargent et al (J Clin Oncol 23: 8664-8670, 2005) concluded that 3-year disease-free survival (DFS) can be considered a valid surrogate (replacement) endpoint for 5-year overall survival (OS) in clinical trials of adjuvant chemotherapy for colorectal cancer. We address the question whether the conclusion holds for trials involving other classes of treatments than those considered by Sargent et al. Additionally, we assess if the 3-year cutpoint is an optimal one. To this aim, we investigate whether the results reported by Sargent et al. could have been used to predict treatment effects in three centrally randomized adjuvant colorectal cancer trials performed by the Japanese Foundation for Multidisciplinary Treatment for Cancer (JFMTC) (Sakamoto et al. J Clin Oncol 22:484-492, 2004). Our analysis supports the conclusion of Sargent et al. and shows that using DFS at 2 or 3 years would be the best option for the prediction of OS at 5 years.
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Prudence Francis, John Crown, Angelo Di Leo, Marc Buyse, Ana Balil, Michael Andersson, Bo Nordenskjöld, Istvan Lang, Raimund Jakesz, Daniel Vorobiof, Jorge Gutiérrez, Guy van Hazel, Stella Dolci, Sophie Jamin, Belguendouz Bendahmane, Richard D Gelber, Aron Goldhirsch, Monica Castiglione-Gertsch, Martine Piccart-Gebhart (2008)  Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial.   J Natl Cancer Inst 100: 2. 121-133 Jan  
Abstract: BACKGROUND: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. METHODS: Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. RESULTS: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). CONCLUSIONS: Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.
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2007
Marc Buyse, Tomasz Burzykowski, Kevin Carroll, Stefan Michiels, Daniel J Sargent, Langdon L Miller, Gary L Elfring, Jean-Pierre Pignon, Pascal Piedbois (2007)  Progression-free survival is a surrogate for survival in advanced colorectal cancer.   J Clin Oncol 25: 33. 5218-5224 Nov  
Abstract: PURPOSE: The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. PATIENTS AND METHODS: Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. RESULTS: In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. CONCLUSION: PFS is an acceptable surrogate for OS in advanced colorectal cancer.
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Marissa N Lassere, Kent R Johnson, Maarten Boers, Peter Tugwell, Peter Brooks, Lee Simon, Vibeke Strand, Philip G Conaghan, Mikkel Ostergaard, Walter P Maksymowych, Robert Landewe, Barry Bresnihan, Paul-Peter Tak, Richard Wakefield, Philip Mease, Clifton O Bingham, Michael Hughes, Doug Altman, Marc Buyse, Sally Galbraith, George Wells (2007)  Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema.   J Rheumatol 34: 3. 607-615 Mar  
Abstract: OBJECTIVE: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. METHODS: After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.
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Joseph R Zelefsky, Muthaiah Srinivasan, Arunava Kundu, Thomas Lietman, John P Whitcher, Kun Wang, Marc Buyse, Emmett T Cunningham (2007)  Hookworm infestation as a risk factor for Mooren's ulcer in South India.   Ophthalmology 114: 3. 450-453 Mar  
Abstract: OBJECTIVE: To investigate the association between Mooren's ulcer and intestinal hookworm infestation in South India. DESIGN: Prospective observational case-control study. PARTICIPANTS: Fifteen patients with Mooren's ulcer and 30 age- and gender-matched controls seen at Aravind Eye Hospital. METHODS: Stool samples from the Mooren's ulcer patients and controls were collected and analyzed for presence of hookworm infestation. MAIN OUTCOME MEASURE: Prevalence of hookworm infestation in Mooren's ulcer patients and controls. RESULTS: There was a statistically significant correlation between intestinal hookworm infestation and the occurrence of Mooren's ulcer (P = 0.009). Retrospective exploratory subgroup analyses suggested that the correlation between intestinal hookworm infestation and the occurrence of Mooren's ulcer in men (P<0.0001) was stronger than the correlation in women, with no statistically significant difference being observed in the prevalence of hookworm infestation between women with Mooren's ulcer and female control subjects (P>0.99). Similarly, when both the Mooren's ulcer and the control subject groups were analyzed retrospectively by age > 50 years or age < 50, subjects with an age over 50 demonstrated a stronger correlation between hookworm infestation and Mooren's ulcer than controls (P = 0.017), whereas there was no statistically significant difference in the prevalence of hookworm infection between Mooren's ulcer subjects and control subjects < or = 50 (P = 0.31). CONCLUSION: Intestinal hookworm infestation appears to be associated with the development of Mooren's ulcer in South India. Although the power of our retrospective exploratory subgroup analyses was limited by multiple testing and small sample sizes, these data suggest further that the correlation between intestinal hookworm infestation and the development of Mooren's ulcer may be greatest in male patients with more advanced age.
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P Piedbois, D Serin, F Priou, P Laplaige, S Greget, E Angellier, E Teissier, J - F Berdah, M Fabbro, B Valenza, P Herait, V Jehl, M Buyse (2007)  Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study.   Ann Oncol 18: 1. 52-57 Jan  
Abstract: BACKGROUND: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. PATIENTS AND METHODS: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC)x6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 x 4, then T 100 mg/m2 x 4 (EC-->T) or the reverse sequence (T-->EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. RESULTS: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC-->T and T-->EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3-4 nail disorders, hand-foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC-->T and T-->EC, respectively. CONCLUSIONS: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T-->EC regimen, the incidence of grade 3-4 events makes it difficult to recommend either dose-dense regimen for further investigation.
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Daniel J Sargent, Smitha Patiyil, Greg Yothers, Daniel G Haller, Richard Gray, Jacqueline Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J Catalano, David Kerr, Erin Green, Harry S Wieand, Richard M Goldberg, Aimery de Gramont (2007)  End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group.   J Clin Oncol 25: 29. 4569-4574 Oct  
Abstract: PURPOSE: The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. METHODS: Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. RESULTS: DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. CONCLUSION: DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.
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Cornelis J A Punt, Marc Buyse, Claus-Henning Köhne, Peter Hohenberger, Roberto Labianca, Hans J Schmoll, Lars Påhlman, Alberto Sobrero, Jean-Yves Douillard (2007)  Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.   J Natl Cancer Inst 99: 13. 998-1003 Jul  
Abstract: Disease-free survival is increasingly being used as the primary endpoint of most trials testing adjuvant treatments in cancer. Other frequently used endpoints include overall survival, recurrence-free survival, and time to recurrence. These endpoints are often defined differently in different trials in the same type of cancer, leading to a lack of comparability among trials. In this Commentary, we used adjuvant studies in colon cancer as a model to address this issue. In a systematic review of the literature, we identified 52 studies of adjuvant treatment in colon cancer published in 1997-2006 that used eight other endpoints in addition to overall survival. Both the definition of these endpoints and the starting point for measuring time to the events that constituted these endpoints varied widely. A panel of experts on clinical research on colorectal cancer then reached consensus on the definition of each endpoint. Disease-free survival--defined as the time from randomization to any event, irrespective of cause--was considered to be the most informative endpoint for assessing the effect of treatment and therefore the most relevant to clinical practice. The proposed guidelines may add to the quality and cross-comparability of future studies of adjuvant treatments for cancer.
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Christine Desmedt, Fanny Piette, Sherene Loi, Yixin Wang, Françoise Lallemand, Benjamin Haibe-Kains, Giuseppe Viale, Mauro Delorenzi, Yi Zhang, d'Assignies Mahasti Saghatchian, Jonas Bergh, Rosette Lidereau, Paul Ellis, Adrian L Harris, Jan G M Klijn, John A Foekens, Fatima Cardoso, Martine J Piccart, Marc Buyse, Christos Sotiriou (2007)  Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.   Clin Cancer Res 13: 11. 3207-3214 Jun  
Abstract: PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. RESULTS: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. CONCLUSION: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
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Aimery de Gramont, Marc Buyse, Jose Cortinas Abrahantes, Tomasz Burzykowski, Emmanuel Quinaux, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Christophe Tournigand (2007)  Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer.   J Clin Oncol 25: 22. 3224-3229 Aug  
Abstract: PURPOSE: In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups. PATIENTS AND METHODS: A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group. RESULTS: Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced. CONCLUSION: Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.
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Marissa Lassere, Kent Johnson, Michael Hughes, Doug Altman, Marc Buyse, Sally Galbraith, George Wells (2007)  Simulation studies of surrogate endpoint validation using single trial and multitrial statistical approaches.   J Rheumatol 34: 3. 616-619 Mar  
Abstract: OBJECTIVE: A schema was recently proposed for assessing the levels of evidence for surrogate validity that included 4 domains: Target, Study Design, Statistical Strength, and Penalties. This report examines one component of the schema. It surveys the literature on methods of statistical validation of surrogate markers and compares these methods head-to-head using simulated datasets. METHODS: Simulated datasets (continuous, multivariate normal) were generated to capture 3 possible relationships of surrogate (S) and true (T) outcome (none, weakly positive, strongly positive) each applied to 4 treatment effects (effect on both surrogate and true outcome, effect on neither, effect on surrogate only, and effect on true outcome only). These datasets were analyzed using single and multitrial statistical approaches, and the results were provided to participants for discussion. RESULTS: The multitrial surrogate threshold effect seemed to capture best the requirement that surrogate validation is demonstrated by a treatment-associated change in the surrogate predicting a treatment-associated change in the outcome. CONCLUSION: There was general agreement that neither a single trial nor any of the single trial statistical methods was adequate to establish surrogate validity. These exercises also showed that summary statistics developed specifically to establish surrogate validity, such as the proportion of the effect explained, were problematic. A sizable statistical research agenda remains, which includes investigating the additional advantage obtained with modeling subject-level data compared to modeling with only trial-level data; and developing and testing multitrial statistical approaches robust to settings with only a few trials.
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Thierry André, Emmanuel Quinaux, Christophe Louvet, Philippe Colin, Erik Gamelin, Olivier Bouche, Emmanuel Achille, Pascal Piedbois, Nicole Tubiana-Mathieu, Arnaud Boutan-Laroze, Michel Flesch, Gérard Lledo, Yves Raoul, Isabelle Debrix, Marc Buyse, Aimery de Gramont (2007)  Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1.   J Clin Oncol 25: 24. 3732-3738 Aug  
Abstract: PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer. PATIENTS AND METHODS: LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m(2)) as a 2-hour infusion, followed by 400 mg/m(2) FU bolus and a 600-mg/m(2) FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m(2) FU 15-minute infusion. The primary end point was disease-free survival (DFS). RESULTS: Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, >or= 2 years; log-rank test for trend P, .0497). CONCLUSION: DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.
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Sherene Loi, Benjamin Haibe-Kains, Christine Desmedt, Françoise Lallemand, Andrew M Tutt, Cheryl Gillet, Paul Ellis, Adrian Harris, Jonas Bergh, John A Foekens, Jan G M Klijn, Denis Larsimont, Marc Buyse, Gianluca Bontempi, Mauro Delorenzi, Martine J Piccart, Christos Sotiriou (2007)  Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.   J Clin Oncol 25: 10. 1239-1246 Apr  
Abstract: PURPOSE: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. MATERIALS AND METHODS: We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. RESULTS: Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. CONCLUSION: The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.
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2006
Thierry André, Daniel Sargent, Josep Tabernero, Michael O'Connell, Marc Buyse, Alberto Sobrero, Jean-Louis Misset, Corrado Boni, Aimery de Gramont (2006)  Current issues in adjuvant treatment of stage II colon cancer.   Ann Surg Oncol 13: 6. 887-898 Jun  
Abstract: BACKGROUND: Adjuvant chemotherapy with 5-fluorouracil modulated by folinic acid, combined with oxaliplatin, has now become an accepted standard of care for patients with stage III colon cancer. In contrast, the use of adjuvant therapy for stage II patients remains controversial, and the identification of reliable prognostic factors to aid therapeutic decision making is crucial. METHODS: The authors critically review the results of clinical trials and meta-analyses investigating the value of adjuvant chemotherapy for stage II patients, emphasizing the heterogeneous nature of this population and the difficulty of performing clinical trials with sufficient power to reliably assess treatment efficacy. They also discuss the evidence concerning potential prognostic factors, particularly molecular markers. RESULTS: Available clinical trial data do not support the routine use of adjuvant chemotherapy for all stage II patients but suggest that it should be considered, particularly for certain high-risk patients. Recent guidelines advocate considering factors such as tumor differentiation, tumor perforation, number of lymph nodes examined, and T stage when assessing the likely benefit:risk ratio. Microsatellite instability and allelic imbalance seem to be strong predictors of good and poor prognosis, respectively, and in the near future, therapeutic decision-making models are likely to be further refined by the inclusion of such molecular markers. CONCLUSIONS: There is growing evidence that the prognosis of certain stage II patients with unfavorable prognostic factors can be improved by adjuvant chemotherapy, and increasingly refined tools are now available to define those most likely to benefit. Referral of stage II patients for individual assessment is strongly recommended.
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Christine Desmedt, Frank El Ouriaghli, Virginie Durbecq, Anne Soree, Maria Antonetta Colozza, Evandro Azambuja, Marianne Paesmans, Denis Larsimont, Marc Buyse, Adrian Harris, Martine Piccart, Philippe Martiat, Christos Sotiriou (2006)  Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients.   Int J Cancer 119: 11. 2539-2545 Dec  
Abstract: Uncontrolled cell proliferation is one of the hallmarks of cancer and the transition from the G1 to S phase is the most commonly reported cell cycle abnormality in tumors. It has been shown that the oncogenic activity of G1 cyclin E (CCNE) can be amplified by generating hyperactive low molecular weight forms (LMW) through elastase-mediated proteolytic processing. Neutrophil elastase (NE) and proteinase 3 (PR3) are 2 proteases that are aberrantly expressed in breast cancer cells and seem to be involved in cell proliferation. In this study, we evaluated the effect of the expression of these 2 proteases in addition to 2 potential intracellular targets of NE (CCNE1 and CCNE2) on clinical outcome in a population of 205 primary breast cancer patients. By univariate analysis, CCNE1, CCNE2, estrogen receptor and grade significantly predicted relapse free interval (RFI). NE and PR3 did not achieve statistical significance. In a multivariate analysis, elevated CCNE2 [hazard ratio (HR) 2.10, p = 0.008] predicted shorter RFI. In subgroup analyses of the tamoxifen-only treated patients, high CCNE1 levels predicted treatment resistance, while high levels of CCNE2 were associated with poor RFI in untreated patients. Investigation of the relationship between CCNE1, CCNE2 and NE did not show any impact on RFI. To conclude, this study was the first to evaluate these markers at the mRNA level by RT-PCR in a series of primary breast cancer patients, and our results confirmed the impact of high CCNE levels on clinical outcome in systemically untreated and of CCNE1 in tamoxifen-only treated early breast cancer patients.
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Christos Sotiriou, Pratyaksha Wirapati, Sherene Loi, Adrian Harris, Steve Fox, Johanna Smeds, Hans Nordgren, Pierre Farmer, Viviane Praz, Benjamin Haibe-Kains, Christine Desmedt, Denis Larsimont, Fatima Cardoso, Hans Peterse, Dimitry Nuyten, Marc Buyse, Marc J Van de Vijver, Jonas Bergh, Martine Piccart, Mauro Delorenzi (2006)  Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.   J Natl Cancer Inst 98: 4. 262-272 Feb  
Abstract: BACKGROUND: Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading. METHODS: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identified differentially expressed genes in a training set of 64 estrogen receptor (ER)-positive tumor samples by comparing expression profiles between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to define the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We identified 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1-3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confidence interval = 2.25 to 5.78; P < .001, log-rank test). CONCLUSIONS: Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value.
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J - L Liénard, E Quinaux, E Fabre-Guillevin, P Piedbois, A Jouhaud, G Decoster, M Buyse (2006)  Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer.   Clin Trials 3: 5. 486-492  
Abstract: PURPOSE: To provide empirical evidence on the impact of on-site initiation visits on the following outcomes: patient recruitment, quantity and quality of data submitted to the trial coordinating office, and patients' follow-up time. PATIENTS AND METHODS: This methodological study was performed as part of a randomized trial comparing two combination chemotherapies for adjuvant treatment of breast cancer. Centers participating to the trial were randomized to either receive systematic on-site visits (Visited group), or not (Non-visited group). RESULTS: The study was terminated after two years, while the main randomized trial continued. Of the 135 centers that had expressed an interest in the trial, only 69 randomized at least one patient (35/68 in the Visited group, 34/67 in the Non-visited group). Almost two-thirds of the patients were entered by 17 centers (10 in the Visited group, seven in the Non-visited group) that accrued more than 10 patients each. None of the prespecified outcomes favored the group of centers submitted to on-site initiation visits (ie, mean number of queries par patient: 6.1 +/- 9.7 versus 5.4 +/- 6.4, respectively for the Visited and Non-visited groups). Spontaneous transmittal of case report forms, although required by protocol, was low in both randomized groups (mean number of pages per patient: 1.5 +/- 2.0 versus 2.1 +/- 2.3, respectively), with investigators submitting about one-third of the expected forms on time (29% and 39%, respectively). LIMITATIONS: This study could not evaluate the impact of repeated on-site visits on clinical outcomes. CONCLUSION: Systematic on-site initiation visits did not contribute significantly to this clinical trial.
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R Glynne-Jones, S Mawdsley, T Pearce, M Buyse (2006)  Alternative clinical end points in rectal cancer--are we getting closer?   Ann Oncol 17: 8. 1239-1248 Aug  
Abstract: BACKGROUND: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible. METHODS: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points. RESULTS: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials. CONCLUSIONS: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.
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P Therasse, E A Eisenhauer, M Buyse (2006)  Update in methodology and conduct of cancer clinical trials.   Eur J Cancer 42: 10. 1322-1330 Jul  
Abstract: Many interesting changes are regularly brought into the methodology of cancer clinical trials. This position paper focuses on three topics which are felt to appear as recurrent problems which deserve more attention from the scientific community. RECIST guidelines were published five years ago and have since then been largely implemented and used in clinical trials. Although the criteria were initially designed for screening phase II trials they have been used also in most phase III studies aiming at determining the efficacy of new treatments. Problems have been identified some of which require further clarifications and others deserve further research which is being undertaken. Overall RECIST is well accepted and a revised version is being considered for 2007. Interim analysis is also an important issue revealed recently through many large adjuvant or advanced trials being prematurely discontinued at the time of an interim analysis. In most instances trials were stopped because of evidence of superiority of the investigational treatment over the standard treatment. Premature discontinuation of trial poses a number of challenges addressed in this paper. Finally, the consequences of the implementation of the EU clinical trial directive are being discussed. The conclusions are without equivoque. There is much less academic research conducted in Europe, there is a lot of discrepancy and inconsistency in the implementation of the directive across member states and there is no apparent direct benefit for the patients.
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Ariel Alonso, Geert Molenberghs, Helena Geys, Marc Buyse, Tony Vangeneugden (2006)  A unifying approach for surrogate marker validation based on Prentice's criteria.   Stat Med 25: 2. 205-221 Jan  
Abstract: Part of the recent literature on the evaluation of surrogate endpoints starts from a multi-trial approach which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between a potential surrogate and a true endpoint, Buyse et al. These authors proposed their methodology based on the simplest cross-sectional case in which both the surrogate and the true endpoint are continuous and normally distributed. Different variations to this theme have been implemented for binary responses, times to event, combinations of binary and continuous endpoints, etc. However, a drawback of this methodology is that different settings have led to different definitions to quantify the association at the individual-level. In the longitudinal setting; Alonso et al. defined a class of canonical correlation functions that can be used to study surrogacy at the trial and individual-level. In the present work, we propose a new approach to evaluate surrogacy in the repeated measurements framework, we also show the connection between this proposal and the previous ones reported in the literature. Finally, we extend this concept to the non-normal case using the so-called 'likelihood reduction factor' (LRF) a new validation measure based on some of the Prentice's criteria. We apply the previous methodology using data from two clinical studies in psychiatry and ophthalmology.
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Christophe Tournigand, Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Marc Buyse, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Aimery de Gramont (2006)  OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study.   J Clin Oncol 24: 3. 394-400 Jan  
Abstract: PURPOSE: In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. PATIENTS AND METHODS: Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS: Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. CONCLUSION: Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.
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Jan Bogaerts, Fatima Cardoso, Marc Buyse, Sofia Braga, Sherene Loi, Jillian A Harrison, Jacques Bines, Stella Mook, Nuria Decker, Peter Ravdin, Patrick Therasse, Emiel Rutgers, Laura J van 't Veer, Martine Piccart (2006)  Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial.   Nat Clin Pract Oncol 3: 10. 540-551 Oct  
Abstract: This Review describes the work conducted by the TRANSBIG consortium in the development of the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial. The goal of the trial is to provide definitive evidence regarding the clinical relevance of the 70-gene prognosis signature, and to assess the performance of this signature compared with that of traditional prognostic indicators for assigning adjuvant chemotherapy to patients with node-negative breast cancer. We outline the background work and the key questions in node-negative early-stage breast cancer, and then focus on the MINDACT trial design and statistical considerations. The challenges inherent in this trial in terms of logistics, implementation and interpretation of the results are also discussed. We hope that this article will trigger further discussion about the difficulties of setting up and analyzing trials aimed at establishing the worth of new methods for better selection of patients for cancer treatment.
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Tomasz Burzykowski, Marc Buyse (2006)  Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation.   Pharm Stat 5: 3. 173-186 Jul/Sep  
Abstract: In many therapeutic areas, the identification and validation of surrogate endpoints is of prime interest to reduce the duration and/or size of clinical trials. Buyse et al. [Biostatistics 2000; 1:49-67] proposed a meta-analytic approach to the validation. In this approach, the validity of a surrogate is quantified by the coefficient of determination Rtrial2 obtained from a model, which allows for prediction of the treatment effect on the endpoint of interest ('true' endpoint) from the effect on the surrogate. One problem related to the use of Rtial2 is the difficulty in interpreting its value. To address this difficulty, in this paper we introduce a new concept, the so-called surrogate threshold effect (STE), defined as the minimum treatment effect on the surrogate necessary to predict a non-zero effect on the true endpoint. One of its interesting features, apart from providing information relevant to the practical use of a surrogate endpoint, is its natural interpretation from a clinical point of view.
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Marc Buyse, Sherene Loi, Laura van't Veer, Giuseppe Viale, Mauro Delorenzi, Annuska M Glas, d'Assignies Mahasti Saghatchian, Jonas Bergh, Rosette Lidereau, Paul Ellis, Adrian Harris, Jan Bogaerts, Patrick Therasse, Arno Floore, Mohamed Amakrane, Fanny Piette, Emiel Rutgers, Christos Sotiriou, Fatima Cardoso, Martine J Piccart (2006)  Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.   J Natl Cancer Inst 98: 17. 1183-1192 Sep  
Abstract: BACKGROUND: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. METHODS: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. RESULTS: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. CONCLUSIONS: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer.
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2005
Daniel J Sargent, Harry S Wieand, Daniel G Haller, Richard Gray, Jacqueline K Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J Catalano, Charles D Blanke, David Kerr, Erin Green, Norman Wolmark, Thierry Andre, Richard M Goldberg, Aimery De Gramont (2005)  Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.   J Clin Oncol 23: 34. 8664-8670 Dec  
Abstract: PURPOSE: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.
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2004
Geert Molenberghs, Tomasz Burzykowski, Ariel Alonso, Marc Buyse (2004)  A perspective on surrogate endpoints in controlled clinical trials.   Stat Methods Med Res 13: 3. 177-206 Jun  
Abstract: The last couple of decades have seen a large amount of activity in the area of surrogate marker and surrogate endpoint validation, both from a clinical and a statistical perspective. Prentice made a pivotal contribution in the context of a single trial. Subsequently, the framework he proposed has been discussed, criticized, and extended. An important class of extensions considers several rather than a single trial. Recently, a lot of work has been done in this so-called hierarchical or meta-analytic framework. In this paper, we review both the single trial and the hierarchical framework. A number of applications, scattered throughout the literature, are brought together. We outline the statistical issues involved in trying to validate surrogate endpoints. Clearly statistical evidence should only be seen as a component in a decision making process that also involves a number of clinical and biological considerations.
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Sherene Loi, Marc Buyse, Christos Sotiriou, Fatima Cardoso (2004)  Challenges in breast cancer clinical trial design in the postgenomic era.   Curr Opin Oncol 16: 6. 536-541 Nov  
Abstract: PURPOSE OF REVIEW: Clinical trials in breast cancer (BC) have seldom taken into consideration molecular heterogeneity, because most have been performed in unselected populations. Hence, their results provide an estimated average benefit for the entire BC population, which may not always be translated to subsets of patients with certain characteristics, let alone to individual patients. Further understanding and acknowledgment of heterogeneity is vital for the development of individualized therapy in BC. New approaches are needed for trial design, patient selection, and choice of endpoints (including surrogate markers). The neoadjuvant setting presents a unique opportunity to test new concepts in a previously untreated patient population, because they may yield preliminary answers in a shorter time than that required in adjuvant trials. RECENT FINDINGS: The importance of patient selection in the development of targeted agents is exemplified by trastuzumab in BC and of gefitinib in lung cancer. Ongoing innovative trials that investigate biologic hypotheses include the BIG-EORTC p53, TOP and FRAGRANCE trials (which study predictive factors for response), and the NNBC-3 and MINDACT trials (which study prognostic factors). SUMMARY: There is an urgent need to break from traditional clinical development and to incorporate new molecular knowledge and translational research in the design of clinical trials. The success of new approaches in BC research critically depends on well-conducted translational research linked to prospective clinical trials, and international collaboration, bringing together human and technological resources.
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A Di Leo, M Buyse, H Bleiberg (2004)  Is overall survival a realistic primary end point in advanced colorectal cancer studies? A critical assessment based on four clinical trials comparing fluorouracil plus leucovorin with the same treatment combined either with oxaliplatin or with CPT-11.   Ann Oncol 15: 4. 545-549 Apr  
Abstract: BACKGROUND: The adequacy of overall survival (OS) as study end point in phase III trials for advanced solid tumors is questionable. The present review highlights the limits of OS as study end point to evaluate the efficacy of new drugs. METHODS: Four phase III clinical trials comparing a fluorouracil-based regimen with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal cancer patients were reviewed. The primary aim of the critical assessment was to explain the lack of OS advantage observed in two of the four trials, despite the presence of increased response rate (RR) and time to progression (TTP). Four possible reasons for the lack of OS benefit (i.e. statistical power, cross-over, magnitude of the effect on RR and TTP, non-tumor-related deaths) were systematically reviewed in the trials, and the detectable 1-year OS difference, assuming a statistical power of 80%, was calculated for each. RESULTS: None of these reasons for the lack of OS advantage in presence of RR and TTP benefits convincingly explained the results of the evaluated trials. Three of the four trials had roughly the same statistical power to detect 1-year OS differences, while the fourth trial was underpowered to detect realistic OS differences. The lack of OS advantage observed in the two oxaliplatin trials is therefore likely fortuitous, and due to lack of statistical power. CONCLUSIONS: Although increase in OS remains the ultimate goal of many clinical trials, the choice of OS benefit as a mandatory requirement to register new compounds can lead to a serious underestimation of a drug's real efficacy.
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Véronique Diéras, Pierre Fumoleau, Gilles Romieu, Michèle Tubiana-Hulin, Moïse Namer, Louis Mauriac, Jean-Paul Guastalla, Eric Pujade-Lauraine, Pierre Kerbrat, Philippe Maillart, Frédérique Pénault-Llorca, Marc Buyse, Pierre Pouillart (2004)  Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.   J Clin Oncol 22: 24. 4958-4965 Dec  
Abstract: PURPOSE: This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. PATIENTS AND METHODS: A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery. RESULTS: A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). CONCLUSION: The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.
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Ariel Alonso, Geert Molenberghs, Tomasz Burzykowski, Didier Renard, Helena Geys, Ziv Shkedy, Fabián Tibaldi, José Cortiñas Abrahantes, Marc Buyse (2004)  Prentice's approach and the meta-analytic paradigm: a reflection on the role of statistics in the evaluation of surrogate endpoints.   Biometrics 60: 3. 724-728 Sep  
Abstract: We put a perspective on the strengths and limitations of statistical methods for the evaluation of surrogate endpoints. Whereas using several trials overcomes some of the limitations of a single-trial framework (Prentice, 1989, Statistics in Medicine 8, 431-440), arguably the evaluation of surrogate endpoints can never be done using only statistical evidence but such evidence should be seen as but one component in a decision-making process that involves, among others, a number of clinical and biological considerations. We briefly present a hierarchical framework that incorporates ideas from Prentice's work and is uniformly applicable to different types of surrogate and true clinical outcomes.
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P Thirion, S Michiels, J P Pignon, M Buyse, A C Braud, R W Carlson, M O'Connell, P Sargent, P Piedbois (2004)  Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.   J Clin Oncol 22: 18. 3766-3775 Sep  
Abstract: PURPOSE: The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials. PATIENTS AND METHODS: Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons. RESULTS: Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms. CONCLUSION: This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.
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Christophe Tournigand, Thierry André, Emmanuel Achille, Gérard Lledo, Michel Flesh, Dominique Mery-Mignard, Emmanuel Quinaux, Corinne Couteau, Marc Buyse, Gérard Ganem, Bruno Landi, Philippe Colin, Christophe Louvet, Aimery de Gramont (2004)  FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.   J Clin Oncol 22: 2. 229-237 Jan  
Abstract: PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULT: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.
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Junichi Sakamoto, Yasuo Ohashi, Chikuma Hamada, Marc Buyse, Tomasz Burzykowski, Pascal Piedbois (2004)  Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.   J Clin Oncol 22: 3. 484-492 Feb  
Abstract: PURPOSE: Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. PATIENTS AND METHODS: This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. RESULTS: The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. CONCLUSION: Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.
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2003
Thierry Andre, Philippe Colin, Christophe Louvet, Erik Gamelin, Olivier Bouche, Emmanuel Achille, Nicolas Colbert, Catherine Boaziz, Pascal Piedbois, Nicole Tubiana-Mathieu, Arnaud Boutan-Laroze, Michel Flesch, Marc Buyse, Aimery de Gramont (2003)  Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.   J Clin Oncol 21: 15. 2896-2903 Aug  
Abstract: PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.
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Marc Buyse, Tomasz Burzykowski, Mahesh Parmar, Valter Torri, George Omura, Nicoletta Colombo, Chris Williams, Pierfranco Conte, Jan Vermorken (2003)  Using the expected survival to explain differences between the results of randomized trials: a case in advanced ovarian cancer.   J Clin Oncol 21: 9. 1682-1687 May  
Abstract: PURPOSE: A meta-analysis of randomized trials in advanced ovarian cancer showed a longer survival with cyclophosphamide, doxorubicin, and cisplatin (CAP) than with cyclophosphamide and cisplatin (CP; P =.009). In contrast, the results of the large International Collaborative Ovarian Neoplasm Study (ICON2) showed no survival difference between CAP and carboplatin (P =.98). In this article, we show how these discrepant results can be reconciled through the estimation of expected survival curves. MATERIALS AND METHODS: A proportional hazards model, fitted to the meta-analysis data, was used to construct the expected survival curve for each treatment arm of the ICON2 trial. Expected survival curves were compared with observed survival curves in the ICON2 trial at all time points using a nonparametric test. RESULTS: The prognostic model for survival obtained in the meta-analysis included extent of residual disease, age, histologic grade, and International Federation of Gynecology and Obstetrics stage. When this model was applied to the ICON2 data, there was no difference between the expected and observed curves in the CAP arm. In contrast, the observed survival curve for carboplatin was far superior to the expected survival curve for CP (P <.01). CONCLUSION: These analyses provide indirect evidence that better results are achieved with carboplatin alone at an optimally tolerated dose, compared with the CP combination at a cisplatin dose of 50 to 60 mg/m2. The expected survival may provide valuable insight when direct comparisons between randomized groups yield discrepant results across different studies.
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Philippe Autier, Peter Boyle, Marc Buyse, Harry Bleiberg (2003)  Is FOB screening really the answer for lowering mortality in colorectal cancer?   Recent Results Cancer Res 163: 254-63; discussion 264-6  
Abstract: In the three trials that tested screening with biennial fecal occult blood test (FOBT), follow-up of control patients for colorectal cancer (CRC) differed: in the Minnesota (United States) trial, the follow-up was equivalent to patients in the intervention groups, while in the Nottingham (United Kingdom) and Funen (Denmark) trials, control patients just received usual care. In the two latter trials, mortality from colorectal cancer was lower in subjects with interval colorectal cancer than in control subjects, while in the Minnesota trial, survival was equivalent in patients with interval CRC and in control patients. We examined whether better disease awareness of subjects allocated to the intervention group contributed to changes in colorectal cancer mortality observed in the FOBT trials. In the Nottingham and Funen trials, we evaluated the amount of colorectal cancer mortality reduction attributable to better survival of subjects in whom an interval colorectal cancer developed. In the Minnesota trial, we examined whether earlier detection of colorectal cancer in control subjects could explain the small (6%) reduction in colorectal cancer mortality observed with biennial FOBT. In the Nottingham and Funen trials, about one-quarter of the reduction in colorectal cancer mortality could be attributed to better awareness of patients with interval colorectal cancer. After correction for the effects of disease awareness, the absolute reduction in colorectal cancer mortality due to FOBT itself was 12% instead of 16%, and was no longer statistically significant (P>0.05). The results from biennial FOBT in the Minnesota trial published in 1993 would probably have been similar to those obtained in the Nottingham and Funen trials if disease awareness had not influenced the stage at diagnosis of colorectal cancers found in the control group. Better awareness of colorectal cancer contributes to the reduction of colorectal cancer mortality and should be encouraged. Because of a study design effect, the decrease in colorectal cancer mortality attributable to the FOBT itself is about 25% lower than that reported in the Nottingham and Funen trials. Therefore, recommending general population screening with biennial FOBT is still an open question.
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Elizabeth Fabre-Guillevin, Pascal Piedbois, Marc Buyse (2003)  Progress in the medical treatment of advanced colorectal cancer.   Expert Rev Anticancer Ther 3: 5. 711-716 Oct  
Abstract: Despite recent progress made in screening, prevention and adjuvant treatment of colorectal cancer, a large proportion of patients with this disease develop local recurrences or distant metastases. The management of these patients requires a multidisciplinary approach. Surgery must be performed whenever possible for metastases confined to the liver or lung. However, in most cases, chemotherapy and supportive care are the only feasible treatments. This review describes the research carried out in this field through randomized trials and meta-analyses aimed at optimizing the efficacy of front-line chemotherapy.
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L Zelek, R Bugat, D Cherqui, G Ganem, P Valleur, R Guimbaud, O Dupuis, T Aziza, P L Fagniez, J Auroux, H Kobeiter, C Tayar, A C Braud, E Haddad, A Piolot, M Buyse, P Piedbois (2003)  Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).   Ann Oncol 14: 10. 1537-1542 Oct  
Abstract: BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.
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2002
Laurent Zelek, Pascal Piedbois, Marc Buyse (2002)  Contribution of meta-analyses to the evaluation of treatments for advanced colorectal cancer.   Expert Rev Anticancer Ther 2: 4. 417-425 Aug  
Abstract: In the last decade, the Meta-Analysis Group in Cancer (formerly Advanced Colorectal Cancer Meta-Analysis Project) has systematically used a meta-analytic to reassess the efficacy and toxicity of various fluoropyrimidine regimens in advanced colorectal cancer, as well as to investigate related questions, such as the relation between tumor response and survival. In this paper, the basic methodology of meta-analysis is reviewed and the findings of seven successive meta-analyses conducted between 1989-2000 by the Meta-Analysis Group in Cancer are summarized. The interested reader can refer to the statistical appendix for details on the methodology used for all meta-analyses.
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Geert Molenberghs, Marc Buyse, Helena Geys, Didier Renard, Tomasz Burzykowski, Ariel Alonso (2002)  Statistical challenges in the evaluation of surrogate endpoints in randomized trials.   Control Clin Trials 23: 6. 607-625 Dec  
Abstract: The validation of surrogate endpoints has been studied by Prentice, who presented a definition as well as a set of criteria that are equivalent if the surrogate and true endpoints are binary. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs proposed to replace the proportion explained by two quantities: (1). the relative effect, linking the effect of treatment on both endpoints, and (2). the adjusted association, an individual-level measure of agreement between both endpoints. In a multiunit setting, these quantities can be generalized to a trial-level measure of surrogacy and an individual-level measure of surrogacy. In this paper, we argue that such a multiunit approach should be adopted because it overcomes difficulties that necessarily surround validation efforts based on a single trial. These difficulties are highlighted.
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2001
P Thirion, P Piedbois, M Buyse, P J O'Dwyer, D Cunningham, A Man, F A Greco, G Colucci, C H Köhne, F Di Constanzo, A Piga, S Palmeri, P Dufour, A Cassano, G Pajkos, R A Pensel, N F Aykan, J Marsh, M T Seymour (2001)  Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.   Br J Cancer 84: 5. 611-620 Mar  
Abstract: Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.
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M Buyse, P Piedbois (2001)  Should Dukes' B patients receive adjuvant therapy? A statistical perspective.   Semin Oncol 28: 1 Suppl 1. 20-24 Feb  
Abstract: The benefit of adjuvant therapy, such as 5-fluorouracil (5-FU) combined with leucovorin, is a matter of debate for patients with Dukes' B colon cancer. Several approaches have been taken to address this issue. Initially, studies were conducted to assess treatment benefits in both Dukes' B and Dukes' C patients. These studies identified an overall benefit of adjuvant treatment and enrolled enough Dukes' C patients to determine a treatment benefit for adjuvant 5-FU/leucovorin in this subpopulation. However, the individual studies were insufficiently powered to detect a treatment benefit in Dukes' B patients. An analysis of four separate studies (National Surgical Adjuvant Breast and Bowel project) compared the benefit of adjuvant treatment in Dukes' B patients with that in Dukes' C patients and showed similar relative reductions in mortality and disease-free survival in Dukes' B and in Dukes' C patients. The Liver Infusion Meta-Analysis Group also reported similar relative benefits from a portal vein infusion of 5-FU-based chemotherapy in Dukes' B and Dukes' C patients. The International Multicenter Pooled Analysis of Colon Cancer Trials B2 study, which combined data from patients with Dukes' B colon cancer in five separate trials, failed to show a statistically significant benefit of adjuvant 5-FU/leucovorin compared with surgery alone. We review the advantages and limitations of different approaches to detect treatment benefits in patients with Dukes' B colon cancer, and we argue that there is a need for a meta-analysis of all adjuvant trials to reliably address this question.
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T André, P Colin, C Louvet, E Gamelin, O Bouche, E Achille, N Colbert, C Boaziz, P Piedbois, N Tubiana-Mathieu, A Boutan-Laroze, M Flesch, V Billiau, M Buyse, A Gramont (2001)  Randomized adjuvant study comparing two schemes of 5-fluorouracil and leucovorin in stage B2 and C colon adenocarcinoma: study design and preliminary safety results. Groupe d'Etude et de Recherche Clinique en Oncologie Radiotherapies.   Semin Oncol 28: 1 Suppl 1. 35-40 Feb  
Abstract: The aim of this randomized open-label study was to compare a bimonthly with a monthly regimen of 5-fluorouracil (5-FU) and leucovorin for the adjuvant treatment of colon and high-rectum adenocarcinoma. The bimonthly regimen was administered for 2 consecutive days every 14 days as d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 as a 2-hour infusion followed by 5-FU bolus of 400 mg/m2 and a 600 mg/m2 5-FU 22-hour continuous infusion (LVSFU2). In the monthly regimen, d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 15-minute infusion followed by a 400 mg/m2 15 minute 5-FU bolus was administered for 5 consecutive days every 28 days (FUFOL). Nine hundred five patients with recently resected stage B2 or C colon or high-rectum adenocarcinoma (inferior pole of the tumor subperitoneal) were recruited into the study. Patients were randomized in a 2 x 2 factorial design to receive either LV5FU2 or FUFOL for 24 or 36 weeks. Characteristics of the patients in the two different treatment groups were similar at baseline. Compliance was good. Mean 5-FU dose intensities were 930 mg/ m2/wk and 463 mg/m2/wk for LVSFU2 and FUFOL, respectively. The incidence of maximal grade III-IV toxicities for LVSFU2 and FUFOL was neutropenia 6% and 16% (P < .001), diarrhea 4% and 10% (P < .001), and mucositis 2% and 7% (P < .001), respectively. Maximum grade III-IV toxicities in the LV5FU2 treatment group were significantly lower than in the FUFOL group (10% v 26%; P < .001). Although patients in the LV5FU2 group received twice the dose of 5-FU compared with those in the FUFOL group, LV5FU2 was shown to be less toxic. Efficacy data will be available in 2001.
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M J Piccart, C Lohrisch, L Duchateau, M Buyse (2001)  Taxanes in the adjuvant treatment of breast cancer: why not yet?   J Natl Cancer Inst Monogr 30. 88-95  
Abstract: The taxanes paclitaxel and docetaxel represent the most active chemotherapeutic agents developed for the treatment of advanced breast cancer in the last decade, and they are now being incorporated into adjuvant chemotherapy trials for lymph node-positive breast cancer with the hope of improving on the results achieved with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or anthracycline-based regimens. So far, three randomized paclitaxel-based adjuvant clinical trials enrolling 3170 women (Cancer and Leukemia Group B [CALGB] 9344), 3060 women (National Surgical Adjuvant Project for Breast and Bowel Cancers [NSABP]-B28), and 524 women (M. D. Anderson), respectively, have been reported with respective median follow-up times of 52, 34, and 43 months. This article critically reviews these three studies and gives an overview of the many other randomized clinical trials, due to accrue more than 17 000 women, which are investigating the potential of taxanes in adjuvant breast cancer therapy. Given that the early promise of taxanes suggested by CALGB 9344 is not yet confirmed by the two other trials, only level 2 evidence has been reached to date in regard to a positive contribution of these agents to breast cancer outcome in the adjuvant setting. It is argued that level 1 evidence is highly desirable before adopting taxane-based regimens in standard practice. It is anticipated that a meta-analysis will be needed to comprehensively define the value of taxanes in early breast cancer, and a new model of international collaboration is proposed to find a balance between the need to offer new, more effective therapies to patients as soon as possible and the danger of drawing wrong, premature conclusions regarding the magnitude of benefit of a new regimen.
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G Molenberghs, H Geys, M Buyse (2001)  Evaluation of surrogate endpoints in randomized experiments with mixed discrete and continuous outcomes.   Stat Med 20: 20. 3023-3038 Oct  
Abstract: A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs pointed to inadequacies of these criteria and suggested a new definition of surrogacy based on (i) the relative effect linking the overall effect of treatment on both endpoints and (ii) an individual-level measure of agreement between both endpoints. Using data from a randomized trial, they showed how a potential surrogate endpoint can be studied using a joint model for the surrogate and the true endpoint. Whereas Buyse and Molenberghs restricted themselves to the fairly simple cases of jointly normal and jointly binary outcomes, we treat the situation where the surrogate is binary and the true endpoint is continuous, or vice versa. In addition, we consider the case of ordinal endpoints. Further, Buyse et al. extended the approach of Buyse and Molenberghs to a meta-analytic context. We will adopt a similar approach for responses of a mixed data type.
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2000
M Buyse, G Molenberghs, T Burzykowski, D Renard, H Geys (2000)  The validation of surrogate endpoints in meta-analyses of randomized experiments.   Biostatistics 1: 1. 49-67 Mar  
Abstract: The validation of surrogate endpoints has been studied by Prentice (1989). He presented a definition as well as a set of criteria, which are equivalent only if the surrogate and true endpoints are binary. Freedman et al. (1992) supplemented these criteria with the so-called 'proportion explained'. Buyse and Molenberghs (1998) proposed replacing the proportion explained by two quantities: (1) the relative effect linking the effect of treatment on both endpoints and (2) an individual-level measure of agreement between both endpoints. The latter quantity carries over when data are available on several randomized trials, while the former can be extended to be a trial-level measure of agreement between the effects of treatment of both endpoints. This approach suggests a new method for the validation of surrogate endpoints, and naturally leads to the prediction of the effect of treatment upon the true endpoint, given its observed effect upon the surrogate endpoint. These ideas are illustrated using data from two sets of multicenter trials: one comparing chemotherapy regimens for patients with advanced ovarian cancer, the other comparing interferon-alpha with placebo for patients with age-related macular degeneration.
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